Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. Screening high-risk individuals for the early detection of colon lesions is an important approach to improving treatment and survival. This application is intended to develop and refine a novel combined endoscopic and proteomic method for evaluating precancerous aberrant crypt foci (ACF) and adenomatous polyps. This methodology aims to establish molecular features that predict, and potentially confer, the efficacy of specific chemoprevention agents. We will use sulindac, currently being tested in an NCI multi-center pilot chemoprevention clinical trial (CPN), as a model chemopreventive agent to develop this methodology. Our proposed studies will address the following issues: (1) The efficacy of sulindac against ACF and adenomas will be tracked in situ using a novel endoscopic imaging/lesion mapping protocol in mice; (2) The proteomic and genomic features of adenomas that predict and/or confer their response to sulindac will be identified; (3) The predictive value of these molecular targets for sulindac efficacy will be evaluated in human colon tissues in a six-week sulindac pilot study. Our hypothesis is that the molecular features of early precancerous lesions and adenomas will predict and potentially confer the efficacy of chemoprevention. Ultimately we envision generating a molecular profile of colon lesions to serve as the basis for assessing risk, designing cancer- prevention strategies customized to the individual and identifying targets for the development of future chemopreventive agents. Although our proposed studies focus on the response to sulindac, this general strategy could be adapted to chemoprevention agents that function through different modes of action. A more comprehensive understanding of how the molecular profile of an individual's colon lesions relates to their response to specific chemopreventive agents could ultimately be used to develop safe and effective strategies that fully realize the promise of chemoprevention for reducing mortality and morbidity related to colon cancer. PUBLIC HEALTH RELEVANCE: We are developing an approach to view the events of colon carcinogenesis and chemoprevention in 'real-time'. It will be possible in principal to determine which subpopulations of early colon lesions develop into tumors, and whether chemoprevention agents suppress the rate of ACF formation, or promote their regression. Our approach is predicted to recapitulate potential clinical situations, in which protein markers can be used to identify individuals with 'high-risk' ACF or adenomas. In addition, a long-term goal of our approach is to customize chemoprevention in human populations based on expression of predictive proteins or genes uncovered in precancerous lesions. Although our proposed studies focus on the response to sulindac, this general strategy could be adapted to chemoprevention agents that function through different modes of action. A more comprehensive understanding of how the molecular profile of an individual's colon lesions relates to their response to specific chemopreventive agents could ultimately be used to develop safe and effective strategies that fully realize the promise of chemoprevention for reducing mortality and morbidity related to colon cancer.